US6033670A - Recombinant live avian vaccine, using as vector the avian infectious laryngotracheitis virus - Google Patents

Recombinant live avian vaccine, using as vector the avian infectious laryngotracheitis virus Download PDF

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US6033670A
US6033670A US08/790,517 US79051797A US6033670A US 6033670 A US6033670 A US 6033670A US 79051797 A US79051797 A US 79051797A US 6033670 A US6033670 A US 6033670A
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virus
iltv
nucleotide sequence
promoter
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Michel Joseph Marie Bublot
Jean-Christophe Francis Audonnet
Eliane Louise Francise Laplace
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Boehringer Ingelheim Animal Health France SAS
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Definitions

  • the present invention relates to vaccines for avian used based on infectious laryngotracheitis virus (ILTV), into which at least one heterologous nucleotide sequence, in particular coding for and expressing an antigenic polypeptide of an avian pathogenic agent, has been inserted by genetic recombination under conditions providing for an immunization leading to an effective protection of the vaccinated animal against the said pathogenic agent.
  • ILTV infectious laryngotracheitis virus
  • the infectious laryngotracheitis virus is an alphaherpes virus (B. Roizman, Arch. Virol. 1992. 123. 425-449) which causes a serious respiratory pathology (infectious laryngotracheitis or ILT) in chickens (L. E. Hanson and T. J. Bagust, Diseases of Poultry 9th edn 1991. pp 485-495. Ames, Iowa State University Press).
  • the vaccines currently available against this illness contain an attenuated strain which can be administered via different routes, including the intranasal, conjunctival and cloacal routes, in the drinking water and by aerosol (L. E. Hanson and T. J. Bagust, Diseases of Poultry 9th Edition 1991. pp 485-495. Ames, Iowa State University Press).
  • ILTV virus Molecular biology studies of the ILTV virus have enabled the viral genome to be characterized (M. A. Johnson et al., Arch. Virol. 1991. 119. 181-198) and a few genes of the virus to be identified (A. M. Griffin, J. Gen. Virol. 1989. 70. 3085-3089), including the genes coding for thymidine kinase (UL23) (A. M. Griffin and M. E. G. Boursnell, J. Gen. Virol. 1990. 71. 841-850; C. L. Keeler et al., Avian Dis. 1991. 35. 920-929), the glycoprotein gB (UL27) (A. M. Griffin, J. Gen. Virol. 1991. 72.
  • An objective of the present invention is to develop an avian vaccine based on recombinant ILTV virus expressing a heterologous gene, this virus being capable of replication and of including an immunity in the vaccinated host while retaining the property of being perfectly harmless.
  • Another objective of the invention is to provide such a vaccine which is, at the same time, especially effective against infectious laryngotracheitis (ILT).
  • ILT infectious laryngotracheitis
  • Another objective of the invention is to provide such a vaccine which can be used in mass vaccination via the mucosal route, for example by means of an aerosol or in the drinking water, such that the replication of the virus in the mucosae enables a mucosal and systemic immunity to be induced.
  • a Mucosal immunity will be especially effective for combating respiratory diseases, and also against other diseases for which the route of entry of the pathogenic agent is mucosal.
  • Another objective of the invention is to provide such a vaccine which can be used both in adults and in young animals.
  • a specific objective is to provide such a vaccine which can be used in mass vaccination via the mucosal route of very young animals such as one-day-old chicks.
  • Another objective of the invention is to provide a vaccine against ILT which has an enhanced efficacy relative to the parent strain and which might even possibly permit the insertion and expression of a heterologous gene.
  • a genomic region which proved entirely suitable as a site for insertion of heterologous genes.
  • NDV Newcastle disease virus
  • MDV glycoprotein gB of the Marek's disease virus
  • IBDV Gumboro disease virus
  • IBV infectious bronchitis virus
  • a subject of the present invention is a recombinant live avian vaccine comprising as vector the ILTV virus comprising at least one heterologous nucleotide sequence, in particular coding for and expressing an antigenic polypeptide of an avian pathogenic agent, inserted into the insertion locus formed by the intergenic region located between the stop codons of ORF B and ORF C of the ILTV virus, which region, in a particular ILTV strain, is defined between nucleotides 908 and 994 in the sequence SEQ ID NO:1.
  • SEQ ID NO:1 While the particular sequence described in the application (SEQ ID NO:1) originates from the vaccinal strain of ILTV T-20 Dec. 8, 1966 (LT BLEN vaccine) obtained from select Laboratories (10026 Main Street P.O. Box 6, Berlin, Md. 21811, USA), it is quite obvious that a person skilled in the art will be able to use the other strains of ILTV, bearing in mind the information given in the present document regarding the vaccinal strain.
  • ORF B and ORF C correspond, respectively, to the UL3.5 and UL4 genes described in the paper by W. Fuchs and T. C. Mettentleiter (J. Gen. Virol. 1996. 77. 2221-2229) of a pathogenic strain obtained from D. Lutticken, Boxmeer, Holland. This paper in no way suggests that this intergenic region might be used as insertion locus.
  • SEQ ID NO:19 reproduces, for this pathogenic strain, the sequence equivalent to SEQ ID NO:1.
  • the intergenic region used as insertion locus in accordance with the invention is included in SEQ ID NO:19 between nucleotides 908 and 994.
  • Heterologous sequence is understood to mean a sequence which does not originate from this insertion locus, that is to say either a sequence whose source is not the ILTV virus or a sequence originating from another genomic region of this virus, or alternatively originating from another ILTV strain, in particular a virulent strain.
  • Insertion into the insertion region is understood, in particular, to mean simple insertion or insertion after total or partial deletion of the insertion locus.
  • CMV immediate early (IE) promoter is understood, in particular, to mean the fragment given in the examples as well as its subfragments that retain the same promoter activity.
  • the CMV IE promoter can be the human promoter (HCMV IE) or the murine promoter (MCMV IE), or alternatively a CMV IE promoter of another origin, for example of monkey, rat, guinea pig or porcine origin.
  • promoters of viral or cellular origin may also be used.
  • promoters of viral origin there may also be mentioned the promoters of genes of the ILTV virus (genes considered to be immediate early (ICP4, ICP27, etc.), early (thymidine kinase, DNA helicase, ribonucleotide reductase, etc.) or late (gB, gD, gC, gK, etc.)), of the Marek's disease virus (MDV), (gB, gC, pp38, pp14, ICP4, Meq, etc., genes) or of the herpes virus of turkeys (gB, gC, ICP4, etc., genes).
  • ICP4 immediate early
  • thymidine kinase DNA helicase
  • ribonucleotide reductase etc.
  • late gB, gD, gC, gK, etc.
  • MDV Marek's disease virus
  • herpes virus of turkeys gB, gC, ICP
  • the nucleotide sequence inserted into the ILTV vector in order to be expressed can be any sequence coding for an antigenic polypeptide of an avian pathogenic agent, capable, when expressed under the favourable conditions brought about by the invention, of providing for an immunization leading to an effective protection of the vaccinated animal against the pathogenic agent.
  • the nucleotide sequences coding for the antigens of interest for a given disease may hence be inserted under the conditions of the invention.
  • This nucleotide sequence inserted into the ILTV vector may also code for an immunomodulatory polypeptide, and in particular a cytokine.
  • the vaccines according to the invention may be used for the in ovo vaccination of one-day-old or older chicks and of adults.
  • Different administration routes may be used: the parenteral route, or the mucosal routes such as the oronasal (drinking water, aerosol), conjunctival (drop in the eye) or cloacal route, with a preference for the routes permitting a mucosal mass vaccination (drinking water, aerosol).
  • the invention proves especially useful both for protection against respiratory pathologies and against systemic pathologies, by blocking the natural routes of entry of the pathogenic agent.
  • the invention may, in particular, be used for the insertion of a nucleotide sequence coding appropriately for an antigenic protein of the NDV virus, and especially the glycoprotein HN or the glycoprotein F.
  • a recombinant live vaccine is thereby obtained affording, in addition to protection against infectious laryngotracheitis, a satisfactory protection against Newcastle disease.
  • the recombinant vaccine against Newcastle disease will preferably contain from 10 to 10 4 pfu/dose.
  • nucleotide sequences coding for antigens of other avian pathogenic agents are inserted into nucleotide sequences coding for antigens of other avian pathogenic agents, and in particular, but without implied limitation, antigens of the Marek's disease virus, especially gB, gC, gD and gH+gL genes (WO-A-90/02803), of the Gumboro disease virus, especially VP2 gene, of the infectious bronchitis virus (IBV), especially S and M genes (M. Binns et al., J. Gen. Virol. 1985. 66. 719-726; M. Boursnell et al., Virus Research 1984. 1.
  • CAV chicken anaemia virus
  • ILTV virus especially the genes coding for gB (A. M. Griffin, J. Gen. Virol. 1991. 72. 393-398), or for gD (M. A. Johnson et al., DNA Sequence--The Journal of Sequencing and Mapping 1995. Vol. 5. pp 191-194. Harwood Academic Publishers GmbH) or for gp60 (K. K. Kongsuwan et al., Virus Genes 1993. 7.
  • the virus of infectious swollen head syndrome or chicken pneumovirosis or turkey rhinotracheitis virus (TRTV); pneumovirus
  • the fusion glycoprotein F Q. Yu et al., J. Gen Virol. 1991. 72. 75-81
  • the attachment glycoprotein G R. Ling et al., J. Gen. Virol. 1991. 73. 1709-1715; K. Juhasz and J. Easton, J. Gen. Virol. 1994. 75 2873-2880.
  • the doses were preferably the same as those for the Newcastle vaccine.
  • ILTV virus in particular in this locus. It is possible, in particular, to insert therein sequences originating from the same virus or from different viruses, which also comprises the insertion of ILTV sequences and sequences from another avian virus. It is also possible to ally therewith sequences coding for immunomodulators, and especially cytokines.
  • the CMV IE promoter is allied with another promoter so that their 5' ends are adjacent (implying transcriptions in opposite directions), which enables two nucleotide sequences, one under the control of the CMV IE promoter and the other under that of the allied promoter, to be inserted into the insertion zone.
  • This construction is noteworthy for the fact that the presence of the CMV IE promoter, and in particular of its activating (enhancer) portion, activates the transcription induced by the allied promoter.
  • the allied promoter can be, in particular, a promoter of a gene of the ILTV virus or of the MDV or HVT virus.
  • An advantageous case of the invention is a vaccine comprising a nucleotide sequence coding for NDV HN and a nucleotide sequence coding for NDV F or an antigen of another avian disease, in particular the ones mentioned above, one of the genes being under the control of the CMV IE promoter and the other under the control of the allied promoter.
  • IVS internal ribosome entry site
  • SVDV swine vesicular disease virus
  • EMCV encephalomyocarditis virus
  • FMDV aphthous fever virus
  • the cassette for expression of two genes would hence have the following minimum structure: promoter--gene 1--IRES--gene 2--polyadenylation signal.
  • the recombinant live vaccine according to the invention may hence comprise, inserted into the insertion locus, an expression cassette comprising in succession a promoter, two or more genes separated pairwise by an IRES, and a polyadenylation signal.
  • the insertion into the locus it is possible to carry out one or more other insertions, one or more mutations or one or more deletions elsewhere in the genome; if the parent strain is virulent, it is possible, for example, to inactivate (by deletion, insertion or mutation) genes involved in the virulence, such as the thymidine kinase gene, the ribonucleotide reductase gene, the gE gene, etc.
  • the insertion into a locus other than the one described in the invention enables other genes to be expressed.
  • a subject of the present invention is also a vaccine against ILT, comprising a recombinant ILTV virus into which an exogenous promoter, especially a strong promoter as described above, has been inserted upstream of the genes coding for major immunogens of ILTV, preferably the genes coding for gB (A. M. Griffin, J. Gen. Virol. 1991. 72, 393-398) or for gD (M. A. Johnson et al., DNA Sequence--The Journal of Sequencing and Mapping 1995. Vol. 5. pp 191-194. Harwood Academic Publishers GmbH) or for gp60 (K. K. Kongsuwan et al., Virus Genes 1993. 7. 297-303).
  • a subject of the present invention is also a multivalent vaccine formula comprising, as a mixture or to be mixed, a vaccine as defined above with another vaccine, and in particular another recombinant live avian vaccine as defined above, these vaccines comprising different inserted sequences, in particular from different pathogens.
  • a subject of the present invention is also a method for preparing the vaccines according to the invention, as emerges from the description.
  • a subject of the present invention is also a method of avian vaccination, comprising the administration of a recombinant live vaccine or of a multivalent vaccine formula as defined above. Its subject is, in particular, such a method for the vaccination in ovo of one-day-old or older chicks and of adults.
  • Different routes of administration of the vaccine may be used (see above), with a preference for the routes permitting a mass vaccination via the mucosal route (aerosol, drinking water), the dose of vaccine preferably being selected between 10 1 and 10 4 per animal.
  • a subject of the present invention is also an ILTV virus comprising at least one heterologous nucleotide sequence as described above, inserted into the insertion locus as defined above.
  • a subject of the present invention is also all or part of the sequence SEQ ID NO:1; parts of this sequence are understood not only to mean the characterized ORFs taken separately or their fragments, but also the intergenic region located between ORF B and ORF C and the fragments located on each side of this intergenic region, which can, where appropriate, include a part of this intergenic region and which may serve as flanking arms for a homologous recombination, a technique which is, moreover, perfectly well known to a person skilled in the art.
  • the flanking arms can have from 100 to 1500 base pairs.
  • FIG. 1 Restriction map of the cloned fragment and position of the ORFs
  • FIG. 2 Sequence of 4161 bp and translation of ORFs A, B, C and D of the Select Laboratories vaccinal strain T-20
  • FIG. 3 Scheme for obtaining the plasmid pEL157
  • FIG. 4 Scheme for obtaining the plasmid pEL024
  • FIG. 5 Scheme for obtaining the plasmid pEL027
  • FIG. 6 Diagram of the plasmid pEL158
  • FIG. 7 Scheme for obtaining the plasmid pCD009
  • FIG. 8 Scheme for obtaining the plasmid pEL070
  • FIG. 9 Diagram of the plasmid pEL159
  • FIG. 10 Sequence of the NDV HN gene
  • FIG. 11 Scheme for obtaining the plasmid pEL030
  • FIG. 12 Diagram of the plasmid pEL160
  • FIG. 13 Diagram of the plasmid pEL033
  • FIG. 14 Diagram of the plasmid pEL161
  • FIG. 15 Diagram of double expression cassette
  • FIG. 16 Diagram of the plasmid pCD011
  • FIG. 17 Diagram of the plasmid pEL163
  • FIG. 18 Sequence of 4161 bp and translation of UL3, 3.5, 4 and 5 of Lutticken's pathogenic strain
  • the virus used as parent virus may be selected from the vaccinal strains described in J. R. Andreasen et al. (Avian Diseases 1990. 34. 646-656) or the strain T-20 Dec. 8, 1966 obtained from Select Laboratories 10026 Main Street P.O. Box 6 Berlin, Md. 21811, USA. It is also possible to use virulent strains such as Lutticken's strain (see above), the strain N-71851 (ATCC VR-783) or the strain 83-2 from USDA, which may be attenuated by known techniques, for example the one described in WO-A-95/08622.
  • the ILTV virus (Select Laboratories strain T20) is cultured on primary chicken kidney cells (CKC); these cells are cultured in MEM medium supplemented with 3% of foetal calf serum (FCS) in 75 cm 2 culture flasks (2 ⁇ 10 5 cells/cm 2 ) one or two days before inoculation.
  • CKC primary chicken kidney cells
  • FCS foetal calf serum
  • a flask of 1000 doses of lyophilized vaccine is resuspended in 10 ml of MEM medium supplemented with 1% of FCS; approximately 0.5 ml of this solution is then applied to the CKC culture.
  • the medium is changed, and the day after, when the cytopathogenic effect (CPE) becomes generalized, the culture flasks are frozen at -70° C.
  • CPE cytopathogenic effect
  • Culture of the ILTV virus may also be carried out on immortalized chicken liver cells, and in particular on the LMH line (W. M. Schnitzlein et al., Avian Diseases 1994. 38. 211-217).
  • the ILTV culture (two 75 cm 2 flasks) is harvested and centrifuged at low speed (5000 rpm in a 20 rotor, Beckman JA21 centrifuge, for 5 minutes) to remove large cell debris. The supernatant is ultracentrifuged (100,000 rpm, TLA100.3 rotor, Beckman TL100 centrifuge, for 1 hour).
  • the pellet is then taken up in 1.6 ml of TEN-SDS (10 mM Tris pH 8.0; 1 mm EDTA; 0.5 NaCl; 0.5% sodium dodecyl sulphate), and 35 ⁇ l of a 20 mg/ml proteinase K solution are then added; the solution is incubated for 3 to 4 hours on a waterbath at 37° C., and the DNA is then extracted 3 times with phenol/chloroform and once with chloroform and is then precipitated with ethanol at -20° C. After centrifugation, the pellet is rinsed with 70% ethanol, dried and resuspended in 200 ⁇ l of TE (10 mM Tris pH 8.0; 1 mM EDTA).
  • TE 10 mM Tris pH 8.0; 1 mM EDTA
  • the nucleic acid concentration is then assayed in a spectrophotometer (OD 260 ).
  • the DNA may be digested directly with the appropriate restriction enzymes and then cloned into the plasmid pBluescript II SK+; similarly, it may also be used in transfection experiments for obtaining a recombinant virus.
  • the donor plasmid composed of a cassette for the expression of a polypeptide inserted between two flanking regions of the insertion locus is digested with a restriction enzyme permitting linearization of the plasmid, and it is then extracted with a phenol/chloroform mixture, precipitation with absolute ethanol and taken up in sterile water.
  • this viral population is cloned at limiting dilution in microplates (96-well) in order to isolate a homogeneous population of recombinant virus.
  • microplates 96-well
  • These plates are left in culture for 1 to 3 days, and the supernatant is then harvested in an empty 96-well plate and the plate containing the supernatants is placed at 4° C. or at -70° C.
  • the cells remaining in the other plates are then fixed with 95% acetone for 20 to 30 minutes at 20° C., or for 5 minutes at room temperature.
  • An indirect immunofluorescence (IIF) reaction is carried out with a monoclonal antibody directed against the polypeptide expressed in order to look for plaques expressing this polypeptide.
  • a further cloning is then performed in the same manner (at limiting dilution in 96-well plates) from the supernatant present in the wells of the plates placed at 4° C. or at -70° C. and corresponding to the wells displaying positive plaques in IIF.
  • 4 successive isolation cycles suffice to obtain recombinant viruses all of whose progeny display a specific fluorescence.
  • the genomic DNA of these recombinant viruses is characterized at molecular level by conventional PCR and Southern blot techniques using the appropriate oligonucleotides and DNA probes.
  • the isolation of recombinant virus may also be carried out by hybridization with a probe specific for the inserted expression cassette.
  • the viral population harvested after transfection is diluted and applied to CKC cells (cultured in Petri dishes) so as to obtain isolated plaques.
  • the infection medium is removed and replaced by 5 ml of MEM medium containing 1% of agarose, kept supercooled at 42° C.
  • the dishes are incubated for 48 to 72 hours at 37° C. in a CO 2 incubator until plaques have appeared.
  • the agarose layer is then removed and a transfer of viral plaques is carried out on a sterile nitrocellulose membrane of the same diameter as the Petri dish used for culturing.
  • This membrane is itself transferred onto another nitrocellulose membrane so as to obtain a reverse "copy" of the first transfer.
  • the plaques transferred onto the latter copy are then hybridized according to the standard techniques known to the person skilled in the art with a digoxigenin-labelled DNA fragment (DNA Labelling Kit, Boehringer Mannheim, CAT # 1175033) of the expression cassette. After hybridization, washes and placing in contact with the visualization substrate, the nitrocellulose membrane is placed in contact with an autoradiographic film. The positive hybridization images on this membrane indicate which plaques are the ones containing recombinant ILTV viruses which have inserted the expression cassette.
  • plaques corresponding to these positive plaques are cut out under sterile conditions from the first nitrocellulose membrane, placed in an Eppendorf tube containing 0.5 ml of MEM medium and sonicated to release the virions from the membrane.
  • the medium containing the Eppendorf tube is then diluted in MEM medium, and the dilutions thereby obtained are used to infect further cultures of CKC cells.
  • the DNA extracted from the ILTV virus was digested with restriction enzyme KpnI for 2 hours at 37° C.
  • the restriction enzyme was then removed by a phenol/chloroform extraction followed by an ethanol precipitation.
  • the fragments resulting from this digestion were then ligated (overnight at 14° C.) with the plasmid pBluescript II Sk+ (pBS-SK+; Stratagene) digested with KpnI and treated with alkaline phosphatase; analysis of the clones obtained after transformation of E. coli DHA5 ⁇ bacteria and culture on dishes of ampicillin-supplemented medium enables KpnI--KpnI inserts of different sizes to be identified, including a fragment of approximately 4.2 kb (plasmid pEL112).
  • the sequence between the stop codons of ORFs B and C can be used to insert cassettes for the expression of polypeptides into the ILTV genome. This sequence is referred to as the insertion locus.
  • the insertion may take place with or without deletion in the intergenic region (see Example 5).
  • the plasmid pEL112 (7116 bp) was digested with the enzymes NotI and SpeI to isolate the 4.5-kb NotI-SpeI fragment.
  • the fragment thus digested was then treated with the DNA polymerase (Klenow fragment) in the presence of dNTP in order to make the ends blunt; after ligation and transformation of E. coli bacteria, the clone pEL156 (4503 bp) was obtained.
  • the oligonucleotides EL001 (SEQ ID NO:2) and EL002 (SEQ ID NO:3) were used as primer for a first chain amplification by Taq polymerase (PCR).
  • the oligonucleotides EL003 (SEQ ID NO:4) and EL004 (SEQ ID NO:5) were used as primer for a second chain amplification by Taq polymerase (PCR).
  • EL001 (SEQ ID NO:2): 5' TATTGCTTTCTACCGAAGTCGG 3'
  • EL003 (SEQ ID NO:4): 5' TCTCCAGAATCGCTGGAGTGTCC 3'
  • EL004 (SEQ ID NO:5): 5' TGCGCGAATTCGTAAGCTTTGATATCCAGTCGACA TAATTTGGTGTTTATTACTTTTA 3'
  • PCRs were performed in the presence of PCR buffer, dNTP, plasmid pEL156 DNA, Taq polymerase and, for the first PCR, the oligonucleotides EL001 and EL002, and for the second PCR, the oligonucleotides EL003 and EL004.
  • Plasmid pEL156 was digested with the enzymes XbaI and XhoI. The two PCR fragments, XbaI and EcoRI (120 bp) and XhoI-EcoRI (85 bp), were ligated overnight at 14° C. with plasmid pEL156 digested with XbaI and XhoI. After transformation of E.
  • the clone pEL157 (4531 bp), comprising an EcoRI-HindIII-EcoRV-SalI polylinker, was obtained (see scheme for obtaining pEL157 in FIG. 3).
  • Plasmid pEL004 was digested with KpnI and HindIII to isolate the 1387-bp KpnI-HindIII fragment containing the complete IBDV VP2 gene. This fragment was cloned into the vector pBS-SK+ previously digested with KpnI and HindIII to give the plasmid pEL023 of 4292 bp (FIG. 4). Plasmid pEL022 was digested with BamHI and NotI to isolate the 1122-bp BamHI-NotI fragment (fragment A).
  • Plasmid pEL023 was digested with BamHI and NotI to isolate the 333-bp BamHI-NotI fragment (fragment B). The fragments A and B were ligated together with the vector pBS-SK+ previously digested with NotI and treated with alkaline phosphatase to give plasmid pEL024 of 4369 bp (FIG. 4).
  • Plasmid pEL024 was digested with NotI to isolate the 1445 bp NotI-NotI fragment. This fragment was ligated with the plasmic pCMV ⁇ (Clontech Cat # 6177-1, FIG. 5) previously digested with NotI to give the plasmid pEL026 of 5095 bp (FIG. 5).
  • Plasmid pEL026 was digested with EcoRI, SalI and XmnI to isolate the 2428 bp EcoRI-SalI fragment. This fragment was ligated with the vector pBS-SK+ previously digested with EcoRI and SalI to give plasmid pEL027 of 5379 bp (FIG. 5).
  • Plasmid pEL027 was digested with EcoRI, SalI and XmnI to isolate the 2428 bp EcoRI-SalI fragment. This fragment was ligated into plasmid pEL157 (see Example 5 and FIG. 3) previously digested with EcoRI an SalI to give plasmid pEL158 of 6950 bp (FIG. 6).
  • the virus VILTV8 was isolated and purified after cotransfection of plasmid pEL158 DNA previously linearized with the enzyme KpnI and the viral DNA, as described in Example 3. This recombinant contains an HCMV-IE/IBDV VP2 cassette in the intergenic site between ORFs B and C of the ILTV virus (see Example 5).
  • Plasmid pCMV ⁇ (Clontech Cat # 6177-1, FIG. 7) was digested with SalI and SmaI to isolate the 3679-bp SalI-SmaI fragment containing the lacZ gene as well as the polyadenylation signal of the SV40 virus late gene. This fragment was inserted into the vector pBS-SK+ previously digested with SalI and EcoRV to give the plasmid pCD002 of 6625 bp (FIG. 7). This plasmid contains the lacZ reporter gene, but no promoter is located upstream of this gene.
  • MCMV virus strain Smith was obtained from the American Type Culture Collection, Rockville, Md., USA (ATCC No. VR-194). This virus was cultured on Balb/C mouse embryo cells and the viral DNA of this virus was prepared as described by Ebeling A. et al. (J. Virol. 1983. 47. 421-433). This viral genomic DNA was digested with PstI to isolate the 2285-bp PstI--PstI fragment. This fragment was cloned into the vector pBS-SK+ previously digested with PstI and treated with alkaline phosphatase to give the plasmid pCD004 (FIG. 7).
  • a double-stranded oligonucleotide was obtained by hybridization of the following two oligonucleotides:
  • MB070 (SEQ ID NO:6) 5' CGAATTCACTAGTGTGTGTCTGCAGGCGGCCGCGTGTGTGTCGACGGTAC 3'
  • MB071 (SEQ ID NO:7) 5' CGTCGACACACACGCGGCCGCCTGCAGACACACACTAGTGAATTCGAGCT 3'
  • This double-stranded oligonucleotide was ligated with the vector pBS-SK+ previously digested with KpnI and SacI to give the plasmid pEL067 (FIG. 8).
  • Plasmid pCD009 was digested with PstI and SpeI to isolate the 1396-bp PstI-SpeI fragment. This fragment was ligated with plasmid pEL067 previously digested with PstI and SpeI to give the plasmid pEL068 of 4297 bp (FIG. 8).
  • Plasmid pEL024 (see Example 6, Section 6.1 and FIG. 5) was digested with HindIII and NotI to isolate the 1390-bp HindIII-NotI fragment (fragment A).
  • Plasmid pEL027 (see Example 6, Section 6.1 FIG. 5) was digested with HindIII and SalI to isolate the 235-bp HindIII-SalI fragment (fragment B).
  • This plasmid hence contains an expression cassette consisting of the MCMV IE promoter, the VP2 gene and the polyA signal of SV40).
  • Plasmid pEL070 was digested with EcoRI, SalI and XmnI to isolate the 3035-bp EcoRI and SalI fragment. This fragment was ligated into plasmid pEL157 (see Example 5 and FIG. 3) previously digested with EcoRI and SalI to give plasmid pEL159 of 7545 bp (FIG. 9). This plasmid permits the insertion of the MCMV IE/IBDV-VP2 expression cassette into the intergenic site between ORFs B and C of the ILTV virus.
  • the virus vILTV9 was isolated and purified after cotransfection of plasmid pEL159 DNA previously linearized with the enzyme BglI and the viral DNA, as described in Example 3.
  • This recombinant contains an MCMV-IE/IBDV VP2 cassette in the intergenic site between ORFs B and C of the ILTV virus (see Example 5).
  • NDV Newcastle disease virus
  • NDV Newcastle disease virus
  • strain Texas The building of a complementary DNA library for the genome of the Newcastle disease virus (NDV), strain Texas, was carried out as described by Taylor J. et al. (J. Virol. 1990. 64. 1441-1450).
  • the sequence of the NDV HN gene contained in this clone is presented in FIG. 10 (SEQ ID NO:8).
  • the plasmid pHN01 was digested with SphI and XbaI to isolate the 2520-bp SphI-XbaI fragment.
  • Plasmid pHN02 was digested with ClaI and PstI to isolate the 700-bp ClaI-PstI fragment (fragment A).
  • a PCR was carried out with the following oligonucleotides:
  • fragment B The fragments A and B were ligated together with the vector pBS-SK+ previously digested with ClaI and HindIII to give the plasmid pEL028 of 3872 bp (FIG. 11). Plasmid pHN02 was digested with BsphI and ClaI to isolate the 425-bp BsphI-ClaI fragment (fragment C).
  • a PCR was carried out with the following oligonucleotides:
  • Plasmid pEL030 was digested with NotI to isolate the 1780 bp NotI--NotI fragment (complete NDV HN gene). This fragment was inserted into the NotI sites of plasmid pEL159 (Example 7, FIG. 9) in place of the 1405-bp NotI--NotI fragment containing the gene coding for the protein VP2 of IBDV; this cloning enables plasmid pEL160 of 7921 bp (FIG. 12) to be isolated. This plasmid permits the insertion of the MCMV-IE/NDV-HN expression cassette into the intergenic site between ORFs B and C of the ILTV virus.
  • the virus vILTV10 was isolated and purified after cotransfection of plasmid pEL160 DNA previously linearized with the enzyme BglI and the viral DNA, as described in Example 3. This recombinant contains an MCMV-IE/NDV HN cassette in the intergenic site between ORFs B and C of the ILTV virus (see Example 5).
  • NDV Newcastle disease virus
  • Plasmid pNDV81 was digested with NarI and PstI to isolate the 1870-bp NarI-PstI fragment (fragment A).
  • a PCR was carried out with the following oligonucleotides:
  • fragment B The fragments A and B were ligated together with the vector pBS-SK+ previously digested with CalI and SalI to give plasmid pEL033 of 4846 bp (FIG. 13).
  • Plasmid pEL033 was digested with NotI to isolate the 1935-bp NotI--NotI fragment (complete F gene). This fragment was inserted into the NotI sites of plasmid pEL159 (Example 7, FIG. 9) in place of the 1405-bp NotI--NotI fragment containing the gene coding for the protein VP2 of IBDV; this cloning enabled plasmid pEL161 of 8074 bp (FIG. 14) to be isolated. This plasmid permits the insertion of the MCMV-IE/NDV-F expression cassette into the intergenic site between ORFs B and C of the ILTV virus.
  • the virus vILTV11 was isolated and purified after cotransfection of plasmid pEL161 DNA previously linearized with the enzyme BglI and the viral DNA, as described in Example 3. This recombinant contains an MCMV-IE/NDV F cassette in the intergenic site between ORFs B and C of the ILTV virus (see Example 5).
  • a double cassette for the expression of two genes can be constructed.
  • Such a construction is outlined in FIG. 15.
  • the 5' end of the two promoters are adjacent so the transcription of the two genes takes place in opposite directions.
  • One of the two promoters is the MCMV IE promoter and the other promoter (referred to allied promoter) is the SV40 promoter (present in the plasmid pSVbeta, Clontech Laboratories, Palo Alto, Calif. 94303-4607, USA).
  • the allied promoter is activated by the enhancer region of the CMV IE promoter.
  • This double expression cassette may then be inserted into the donor plasmid described above (pEL157 described in Example 5 and shown in FIG. 3).
  • CD001 (D
  • CD002 (SEQ ID NO:16) 5' TTCGGGACATTTTCGCGG 3'
  • CD003 (SEQ ID NO:17) 5' TATATGGCGTTAGTCTCC 3'
  • CD004 (SEQ ID NO:18) 5' TTGCGAGCTCGCGGCCGCTTATTACACAGCATCATCTTCTG 3'
  • Plasmid pCD011 was digested with NotI to isolate the 2608-bp NotI--NotI fragment (complete MDV gB gene). This fragment was inserted into the NotI sites of plasmid pEL159 (Example 7, FIG. 9) in place of the 1405-bp NotI--NotI fragment containing the gene coding for the protein VP2 of IBDV; this cloning enabled plasmid pEL163 of 8749 bp (FIG. 17) to be isolated. This plasmid permits the insertion of the MCMV-IE/MDV-gB expression cassette into the intergenic site between ORFs B and C of the ILTV virus.
  • the virus vILTV12 was isolated and purified after cotransfection of plasmid pEL161 DNA previously linearized with the enzyme BglI and the viral DNA, as described in Example 3.
  • This recombinant contains an MCMV-IE/MDV gB cassette in the intergenic site between ORFs B and C of the ILTV virus (see Example 5).
  • ILTV viruses expressing at a high level the membrane (M) or spike (S), or part of spike (S1 or S2) or nucleocapsid (N) proteins of the avian infectious bronchitis virus (IBV).
  • M membrane
  • S spike
  • S1 or S2 spike
  • N nucleocapsid
  • ILTV viruses expressing at a high level immunogens of CAV (and in particular a double cassette for the expression of the genes coding for VP1 and VP2), of the chicken pneumovirosis virus or of other avian pathogenic agents, or alternatively immunomodulatory peptides, and in particular cytokines.
  • the recombinant viruses obtained according to the invention are produced on embryonated eggs.
  • the harvested viral solution is then diluted in a stabilizing solution for lyophilization, distributed on the basis of 1000 vaccinal does per vial and lastly lyophilized.

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